Gastric cancer is one of the most common cancers in humans. It has been the second most cause of cancer death in the world during the twentieth century. Although decreasing in numbers of incidence over the past years, gastric cancer is still one of the most frequent causes of cancer-related deaths worldwide. Especially in Asia the prevalence of gastric cancer remains higher than in the western world.
Generally the prognosis for gastric cancer is still poor. This is in part due to the fact, that the disease is often diagnosed in a late stage. Furthermore there is a high rate of recurrence after initial therapy of the carcinoma. Therefore an important step in managing gastric cancer is diligent monitoring of the disease course.
First this means to determine the stage of the patients disease. The determination of the stage has a potential prognostic value and can be used to design an optimal therapy. Although in gastric cancer pathological staging is generally preferable over clinical staging, the advantage of clinical staging is, that it does not depend on surgically invasive methods. Thus characterization of the molecular biological properties of a particular tumor could lead to a more specific and efficient therapy. According to the molecular basics of the tumor a therapy could be tailored to avoid recurrence of the disease.
Furthermore monitoring means a close follow up of the disease after initial therapy. On the basis of classical clinical methods the detection of the recurrence of tumors is quite insensitive, so that the disease has reached a progressed stage until it is found. The follow up could as well be carried out on a molecular level, to recognize the recurrence of the disease as early as possible.
There is a series of tools to assess primary diagnosis in tumors such as gastrointestinal tumors. Yet, due to the diversity of the molecular characteristics of tumors, the outcome of detected tumor may vary widely. For assessing prognosis and tailoring an adequate therapy further characterization of the tumors is indispensable. In a series of tumors prediction about the course and the treatment necessary can be made by testing for the level of expression of several tumor markers. Based upon this prognosis it is possible to choose a treatment for the particular tumor to ensure the best chances for the patient gathered with lowest necessary therapeutical burden. For gastric cancer the classic ways of staging and grading of the tumor allow only for a restricted prognosis, so that actually consuming therapies are put through to avoid recurrence of tumors. If the aggressiveness of tumors could be diagnosed on the basis of molecular markers, the therapy could be better suited to the needs of the special case.
Some marker proteins for diagnosing of gastric cancer have been identified to date. For a reliable prognosis of the disease course of gastric cancer in individual patients a series of tumor related cell cycle regulatory proteins have been tested. Yet no correlation between tumor markers and the prognosis of disease course could be found up to now.
Molecular markers being useful for the prognosis of the disease course in a wide range of tumors are the inhibitors of cyclin-dependent kinases. The key role of cyclin dependent kinase inhibitors in the cell cycle is the regulation of the activity of the cyclin dependent kinases. This regulation is brought forth by binding of the CKI to specific binding sites on their respective binding partner cyclin dependent kinases. Two main families of CKI have been identified, the members of which share a high percentage of sequence homology and the binding specificity to their binding partners. The first family of cyclin-dependent kinase inhibitors binds specifically to and inhibits cdk2. The second family in contrast preferentially binds to and inhibits cdk4 and cdk6. Members of the second family of CKI are for example p16, p15, p18 and p19/20.
One candidate marker for the prognosis of disease course, that has proven useful in several tumor types, is the MTS1 protein (p16INK4A). p16 has been reported to be valuable marker for assessment of the biological behavior and prognosis for example in nasopharyngeal carcinoma (Wang, L. et al.; 1999, 30 (4), 394-396) and breast cancer. In these cases loss of p16 expression indicates poor prognosis for patients.
Another cyclin-dependent kinase inhibitor p27 turned out to be a candidate for a prognostic marker in tumors.
The level of expression of p27 protein has been described to allow assessment of prognosis in a wide range of tumors (US6180333). In the case of p27, expression of the protein within the samples is associated with better prognosis. The cumulative survival of patients that did not express p27 in the tumor tissue is significantly reduced compared to the patients that showed p27 expression. In gastrointestinal tumors there are hints for correlations between tumor progression and reduced levels of p27 protein (Migaldi M., et al., Pathol Res Pract 2001;197(4):231-6), yet there are difficulties in assessing reliable prognosis in gastrointestinal tumors using this marker protein (Feakins R M., et al., Cancer 2000 Oct. 15;89(8): 1684-91).
Especially in gastrointestinal cancers there is need for molecular markers, that allow for assessment of prognosis, diligent monitoring, building a strategy for therapy and finally sensitive followup.
This is provided by the method claimed according to the present invention.